The advent of commercially available type-specific serologies, in combination with counseling and antiviral therapy has provided the tools to initiate more active preventative strategies for the reduction of HSV-2 transmission. An effective HSV vaccine could enhance these tools even more. However, to effectively implement a preventative strategy better understanding is needed of the biological and behavioral correlates of HSV-2 transmission. The specific aims of this proposal are: 1) To determine, based on the duration of sex partnerships prior to transmission, behavioral, virologic, and immunologic risk factors (such as source partner's lack of awareness of infection, condom use, high viral shedding rates and serostatus) which confer increased risk of HSV transmission, 2) to examine the behavioral, virologic and immunologic aspects of persistently HSV-2 discordant partnerships (non-transmitters). The hypothesis are that most HSV-2 infections are acquired within a short time of initiation of the sex partnership, from persons unaware that they have the infection, and lack of condom use and high viral shedding rates in the source partners are also associated with high risk of HSV transmission to sex partners. The study will be documented by restriction enzyme analysis. Behavioral information will be elicited by interview with both partners and biologic correlates will be assessed using viral isolation, HSV DNA PCR and type-specific serologies. Shedding rate in source partners will be evaluated prospectively using daily viral cultures. Behavioral, virologic and immunologic aspects of protection from transmission will also be assessed in 250 HSV-2 discordant couples. The analysis will use the Cox proportional hazards model to assess the relative risk of characteristics associated with HSV-2 transmission. In exploratory analyses, local and systemic immune responses of HSV-2 exposed but infected persons, and HSV-2 transmitters versus non-transmitters will be assessed. Findings from this study will characterize persons at high risk for transmitting and at high risk for acquiring genital herpes: prevention efforts should focus on these groups.